TY - JOUR
T1 - Steady-state activation and modulation of the concatemeric α1β2γ2L GABAA receptor
AU - Germann, Allison L.
AU - Pierce, Spencer R.
AU - Burbridge, Ariel B.
AU - Steinbach, Joe Henry
AU - Akk, Gustav
N1 - Funding Information:
as adopted and promulgated by the National Institutes of Health. The animal protocol was approved by the Animal Studies Committee of Washington University in St. Louis (approval no. 20170071).
Funding Information:
This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grant GM108580] and funds from the Taylor Family Institute for Innovative Psychiatric Research. https://doi.org/10.1124/mol.119.116913.
Publisher Copyright:
Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.
PY - 2019/9
Y1 - 2019/9
N2 - The two-state coagonist model has been successfully used to analyze and predict peak current responses of the γ-aminobutyric acid type A (GABAA) receptor. The goal of the present study was to provide a model-based description of GABAA receptor activity under steady-state conditions after desensitization has occurred. We describe the derivation and properties of the cyclic three-state resting-active-desensitized (RAD) model. The relationship of the model to receptor behavior was tested using concatemeric α1β2γ2 GABAA receptors expressed in Xenopus oocytes. The receptors were activated by the orthosteric agonists GABA or β-alanine, the allosteric agonist propofol, or combinations of GABA, propofol, pentobarbital, and the steroid allopregnanolone, and the observed steady-state responses were compared with those predicted by the model. A modified RAD model was employed to analyze and describe the actions on steady-state current of the inhibitory steroid pregnenolone sulfate. The findings indicate that the steady-state activity in the presence of multiple active agents that interact with distinct binding sites follows standard energetic additivity. The derived equations enable prediction of peak and steady-state activity in the presence of orthosteric and allosteric agonists, and the inhibitory steroid pregnenolone sulfate.
AB - The two-state coagonist model has been successfully used to analyze and predict peak current responses of the γ-aminobutyric acid type A (GABAA) receptor. The goal of the present study was to provide a model-based description of GABAA receptor activity under steady-state conditions after desensitization has occurred. We describe the derivation and properties of the cyclic three-state resting-active-desensitized (RAD) model. The relationship of the model to receptor behavior was tested using concatemeric α1β2γ2 GABAA receptors expressed in Xenopus oocytes. The receptors were activated by the orthosteric agonists GABA or β-alanine, the allosteric agonist propofol, or combinations of GABA, propofol, pentobarbital, and the steroid allopregnanolone, and the observed steady-state responses were compared with those predicted by the model. A modified RAD model was employed to analyze and describe the actions on steady-state current of the inhibitory steroid pregnenolone sulfate. The findings indicate that the steady-state activity in the presence of multiple active agents that interact with distinct binding sites follows standard energetic additivity. The derived equations enable prediction of peak and steady-state activity in the presence of orthosteric and allosteric agonists, and the inhibitory steroid pregnenolone sulfate.
UR - http://www.scopus.com/inward/record.url?scp=85070661219&partnerID=8YFLogxK
U2 - 10.1124/mol.119.116913
DO - 10.1124/mol.119.116913
M3 - Article
C2 - 31263018
AN - SCOPUS:85070661219
SN - 0026-895X
VL - 96
SP - 320
EP - 329
JO - Molecular pharmacology
JF - Molecular pharmacology
IS - 3
ER -